Background Right ventricular (RV) failure after left ventricular assist device (LVAD) placement is a serious complication and is difficult to predict. In the era of destination therapy and the total artificial heart, predicting post-LVAD RV failure requiring mechanical support is extremely important. Methods We reviewed patient characteristics, laboratory values, and hemodynamic data from 266 patients who underwent LVAD placement at the University of Pennsylvania from April 1995 to June 2007. Results Of 266 LVAD recipients, 99 required RV assist device (BiVAD) placement (37%). We compared 36 parameters between LVAD (n=167) and BiVAD patients (n=99) to determine preoperative risk factors for RV assist device (RVAD) need. By univariate analysis, 23 variables showed statistically significant differences between the two groups (P ≤ 0.05). By multivariate logistic regression, cardiac index ≤ 2.2 L/min·m2 (odds ratio [OR] 5.7), RV stroke work index ≤ 0.25 mmHg·mL/m2 (OR 5.1), severe preoperative RV dysfunction (OR 5.0), preoperative creatinine ≥ 1.9 mg/dL (OR 4.8), previous cardiac surgery (OR 4.5), and systolic blood pressure ≤ 96 mmHg (OR 2.9) were the best predictors of RVAD need. Conclusions The most significant predictors for RVAD need were cardiac index, RV stroke work index, severe preoperative RV dysfunction, creatinine, previous cardiac surgery, and systolic blood pressure. Using these, we constructed an algorithm which can predict which LVAD patients will require RVAD with greater than 80% sensitivity and specificity.

Objective It is generally accepted that patients who require biventricular mechanical support (BiVAD) have poorer outcomes than those requiring isolated left ventricular support (LVAD). However, it is unknown how the timing of BiVAD insertion affects outcomes. We hypothesized that planned BiVAD insertion improves survival compared to delayed conversion of LVAD to BiVAD. Methods We reviewed and compared outcomes of 266 patients undergoing LVAD or BiVAD placement at the University of Pennsylvania from April 1995 to June 2007. We subdivided BiVAD patients into planned BiVAD (P-BiVAD) and delayed BiVAD (D-BiVAD) groups, based on the timing of RVAD insertion. We defined D-BiVAD as any failure of isolated LVAD support. Results Of 266 LVAD patients, 99 required BiVAD (37%). We compared preoperative characteristics, successful bridging to transplant, survival to hospital discharge, and Kaplan-Meier one-year survival between P-BiVAD (n=71) and D-BiVAD (n=28) groups. Preoperative comparison showed that patients who ultimately require biventricular support have similar preoperative status. LVAD (n=167) outcomes in all categories exceeded both P-BiVAD and D-BiVAD outcomes. Further, P-BiVAD patients had superior survival to discharge than D-BiVAD patients (51% v 29% p<0.05). One-year and long-term Kaplan-Meier survival distribution confirmed this finding. There was also a trend towards improved bridging to transplant in P-BiVAD (n=55) vs. D-BiVAD (n=22) patients (65% v 45% p=0.10). Conclusion When patients at risk for isolated LVAD support failure are identified, proceeding directly to BiVAD implantation is advised, as early institution of biventricular support results in dramatic improvement in survival.

Background Critical limb ischemia (CLI) is a manifestation of peripheral artery disease (PAD) that carries significant mortality and morbidity risk in humans, although its genetic determinants remain largely unknown. We previously discovered two overlapping quantitative trait loci (QTL) in mice, Lsq-1 and Civq-1, that affected limb muscle survival and stroke volume following femoral artery or middle cerebral artery ligation, respectively. Here we report that a Bag3 variant (Ile81Met) segregates with tissue protection from hindlimb ischemia (HLI). Methods We treated mice with either adeno-associated viruses (AAV) encoding a control (GFP), or two BAG3 variants, namely Met81 or Ile81, and subjected the mice to hindlimb ischemia. Results We found that the BAG3 Ile81Met variant in the C57BL/6 (BL6) mouse background segregates with protection from tissue necrosis in a shorter congenic fragment of Lsq-1 (C.B6-Lsq1-3). Treating BALB/c mice with AAV encoding the BL6 BAG3 variant (Ile81) (n=25) displayed reduced limb tissue necrosis and increased limb tissue perfusion compared to Met81- (n=25) or GFP- (n=29) expressing animals. BAG3Ile81, but not BAG3Met81, improved ischemic muscle myopathy and muscle precursor cell differentiation and improved muscle regeneration in a separate, toxin-induced model of injury. Systemic injection of AAV-BAG3Ile81 (n=9), but not BAG3Met81 (n=10) or GFP (n=5), improved ischemic limb blood flow, limb muscle histology, and restored muscle function (force production). Compared to BAG3Met81, BAG3Ile81 displayed improved binding to the small heat shock protein (HspB8) in ischemic skeletal muscle cells and enhanced ischemic muscle autophagic flux. Conclusions Taken together, our data demonstrate that genetic variation in BAG3 plays an important role in the prevention of ischemic tissue necrosis. These results highlight a pathway that preserves tissue survival and muscle function in the setting of ischemia.

Objective The primary preclinical model of peripheral artery disease (PAD), which involves acute limb ischemia (ALI), can result in appreciable muscle injury that is attributed to the acuity of the ischemic injury. A less acute model of murine limb ischemia using ameroid constrictors (AC) has been developed in an attempt to mimic the chronic nature of human disease. However, there is currently little understanding of how genetics influence muscle injury following subacute arterial occlusion in the mouse. Methods We investigated the influence of mouse genetics on skeletal muscle tissue survival, blood flow, and vascular density by subjecting two different mouse strains, C57BL/6 (BL6) and BALB/c, to ALI or subacute limb ischemia (SLI) using single (1AC) or double (2AC) ameroid constrictor placement on the femoral artery. Results Similar to ALI, the 2AC model resulted in significant tissue necrosis and limb perfusion deficits in genetically susceptible BALB/c but not BL6 mice. In the 1AC model, no outward evidence of tissue necrosis was observed, and there were no differences in limb blood flow between BL6 and BALB/c. However, BALB/c mice displayed significantly greater muscle injury, as evidenced by increased inflammation and myofiber atrophy, despite having no differences in CD31+ and SMA+ vascular density and area. BALB/c mice also displayed significantly greater centralized myonuclei, indicating increased muscle regeneration. Conclusions The susceptibility of skeletal muscle to ischemia-induced injury is at least partly independent of muscle blood flow and vascular density, consistent with a muscle cell autonomous response that is genetically determined. Further development of preclinical models of PAD that more accurately reflect the nature of the human disease may allow more accurate identification of genetic targets for therapeutic intervention.

Background While hemodynamic monitoring is often performed following coronary artery bypass grafting (CABG), the relationship between postoperative central venous pressure (CVP) measurement and clinical outcomes is unknown. Methods Detailed clinical data were analyzed from 2,390 randomly selected patients undergoing high risk CABG or CABG/valve at 55 hospitals participating in the Society of Thoracic Surgeons' National Cardiac Surgery Database from 2004 to 2005. Eligible patients underwent elective/urgent isolated CABG with an ejection fraction < 40%, or elective/urgent CABG at age ≥65 years with diabetes or a glomerular filtration rate 60 mL/min per 1.73 m2. Correlation between post-operative CVP and in-hospital / 30-day mortality and renal failure was assessed as a continuous variable, both unadjusted and after adjusting for important clinical factors using logistic regression modeling. Results Mean age was 72 years, 54% of patients had diabetes mellitus, 49% were urgent procedures, and mean cardiopulmonary bypass time was 105 minutes. Patients’ CVP 6 hours post-operation was strongly associated with in-hospital and 30 day mortality: odds ratio (OR) 1.5 (95% confidence interval [CI] 1.23, 1.87) for every 5 mmHg increase in CVP, p<0.0001. This association remained significant after risk-adjustment for cardiac index: adjusted OR 1.44 (95% CI 1.10, 1.89), p<0.01. A model adjusting for cardiac index also revealed increased incidence of mortality or renal failure: adjusted OR 1.5 (95% CI 1.28, 1.86) for every 5 mmHg increase in CVP, p<0.0001. Conclusion Patients’ central venous pressure at 6 hours following CABG surgery was highly predictive of operative mortality or renal failure, independent of cardiac index and other important clinical variables. Future studies will need to assess whether post-operative CVP can be used to guide intervention and improve outcomes.